Keeping fat out of muscle - Role of Branched Amino AcidsAmino Acids in Insulin Resistance

总结 2型糖尿病及其前体胰岛素抵抗（IR）持续上升，并导致心血管并发症 国际吧IR的潜在机制仍不完全清楚。流行病学研究 一致地揭示了高血压患者血浆支链氨基酸（BCAAs）升高的特征， 糖尿病或IR，以及将继续发展IR的受试者。 显示BCAA催化剂IR全身性抑制，而BCAA催化剂IR全身性激活 (most通常与BCKDK的特异性抑制剂BT 2一起使用，BT 2反过来又抑制BCKDH，BCKDH是BCAA的限速步骤 因此，对靶向该途径存在强烈的兴趣，并且多种药物组合物可以改善IR。 公司正在开发新的基于BT 2的分子系列。尽管做出了这些努力， BCAA催化剂改善IR仍然令人惊讶地未知。在寻找潜在机制的过程中，我们 发现BT 2促进血管舒张和降低血压，并且它不依赖于一氧化氮 内皮细胞产生的一氧化氮（NO），表明BT 2作用于平滑肌细胞（SMC）。 大量文献表明，胰岛素刺激的血管舒张有助于葡萄糖摄取，但如何 胰岛素促进血管舒张的作用仍不完全清楚。这些意见和其他初步意见 数据使我们假设胰岛素促进SMC中的BCAA catalysts，反过来促进 血管舒张和葡萄糖耐量，从而解释了BCAA全身激活的代谢益处 猫我们将用新的遗传小鼠模型来检验这一假设;用最先进的血管内皮细胞， 生理学分析;高胰岛素正葡萄糖钳夹;以及人类研究，以测试这种影响。 对人体血管张力和反应性的影响。这些高度集中的研究将阐明支链氨基酸的作用 在调节血管反应性和葡萄糖耐量方面，包括人体研究。

SUMMARY Type 2 Diabetes and its precursor insulin resistance (IR) continue to rise and drive cardiovascular complications worldwide. The mechanisms underlying IR remain incompletely understood. Epidemiological studies have consistently revealed a signature of elevated plasma branched chain amino acids (BCAAs) in patients with diabetes or IR, as well as subjects who will go on to develop IR. Mouse studies in laboratories worldwide have shown that systemic suppression of BCAA catabolism worsens IR, while systemic activation of BCAA catabolism (most often with BT2, a specific inhibitor of BCKDK, which in turn inhibits BCKDH, the rate-limiting step of BCAA catabolism) improves IR. There is thus strong interest in targeting this pathway, and multiple pharmaceutical companies are developing novel BT2-based molecule series. Despite these efforts, how systemic activation of BCAA catabolism improves IR remains surprisingly unknown. In our search for potential mechanisms, we discovered that BT2 promotes vasodilation and lowers blood pressure, and that it does so independently of nitric oxide (NO) production by endothelial cells, suggesting that BT2 acts on smooth muscle cells (SMCs) instead. Substantial literature indicates that insulin-stimulated vasodilation contributes to glucose uptake, although how insulin promotes vasodilation remains incompletely understood. These observations and additional preliminary data have led us to the hypothesis that insulin promotes BCAA catabolism in SMCs, in turn promoting vasodilation and glucose tolerance, thereby explaining the metabolic benefits of systemic activation of BCAA catabolism. We will test this hypothesis with novel genetic murine models; with state-of-the-art vascular physiology assays; with hyperinsulinemic euglycemic clamps; and with human studies to test the impact of this pathway on human vascular tone and reactivity. These highly focused studies will elucidate the role of BCAA catabolism in regulating vascular reactivity and glucose tolerance, including human studies.